Vicagrel
(Synonyms: 维卡格雷) 目录号 : GC37901
Vicagrel 氯吡格雷的醋酸衍生物，是一种 P2Y12 血小板抑制剂，可用于治疗血栓形成，羧酸酯酶 2 (CES2) 的底物。Vicagrel 具有良好的安全性和优异的抗血小板活性，可作为抗血小板药物。
Cas No.:1314081-53-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Vicagrel, an acetate derivative of Clopidogrel, is a P2Y12 platelet inhibitor potentially for the treatment of thrombosis, the substrate of carboxylesterase 2 (CES2)[1]. Vicagrel demonstrates a favorable safety profile and excellent anti-platelet activity, which could be an anti-platelet drug and for the unmet medical needs of cardiovascular diseases[2].
[1]. Liu C, et al. Pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing. Eur J Pharm Sci. 2019 Jan 15;127:151-160. [2]. Li X, et al. Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers. Front Pharmacol. 2018 Jun 20;9:643.
| Cas No. | 1314081-53-2 | SDF | |
| 别名 | 维卡格雷 | ||
| Canonical SMILES | O=C(OC)[C@@H](N1CCC2=C(C=C(OC(C)=O)S2)C1)C3=CC=CC=C3Cl | ||
| 分子式 | C18H18ClNO4S | 分子量 | 379.86 |
| 溶解度 | DMSO: 250 mg/mL (658.14 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6325 mL | 13.1627 mL | 26.3255 mL |
| 5 mM | 0.5265 mL | 2.6325 mL | 5.2651 mL |
| 10 mM | 0.2633 mL | 1.3163 mL | 2.6325 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Vicagrel is hydrolyzed by Raf kinase inhibitor protein in human intestine
Biopharm Drug Dispos 2022 Dec;43(6):247-254.PMID:36519186DOI:10.1002/bdd.2340.
As an analog of clopidogrel and prasugrel, Vicagrel is completely hydrolyzed to intermediate thiolactone metabolite 2-oxo-clopidogrel (also the precursor of active thiol metabolite H4) in human intestine, predominantly by AADAC and CES2; however, other unknown Vicagrel hydrolases remain to be identified. In this study, recombinant human Raf kinase inhibitor protein (rhRKIP) and pooled human intestinal S9 (HIS9) fractions and microsome (HIM) preparations were used as the different enzyme sources; prasugrel as a probe drug for RKIP (a positive control), Vicagrel as a substrate drug of interest, and the rate of the formation of thiolactone metabolites 2-oxo-clopidogrel and R95913 as metrics of hydrolase activity examined, respectively. In addition, an IC50 value of inhibition of rhRKIP-catalyzed Vicagrel hydrolysis by locostatin was measured, and five classical esterase inhibitors with distinct esterase selectivity were used to dissect the involvement of multiple hydrolases in Vicagrel hydrolysis. The results showed that rhRKIP hydrolyzed Vicagrel in vitro, with the values of Km , Vmax , and CLint measured as 20.04 ± 1.99 μM, 434.60 ± 12.46 nM/min/mg protein, and 21.69 ± 0.28 ml/min/mg protein, respectively, and that an IC50 value of locostatin was estimated as 1.24 ± 0.04 mM for rhRKIP. In addition to locostatin, eserine and vinblastine strongly suppressed Vicagrel hydrolysis in HIM. It is concluded that RKIP can catalyze the hydrolysis of Vicagrel in the human intestine, and that Vicagrel can be hydrolyzed by multiple hydrolases, such as RKIP, AADAC, and CES2, concomitantly.
Vicagrel enhances aspirin-induced inhibition of both platelet aggregation and thrombus formation in rodents due to its decreased metabolic inactivation
Biomed Pharmacother 2019 Jul;115:108906.PMID:31060007DOI:10.1016/j.biopha.2019.108906.
Both aspirin and Vicagrel are effective antiplatelet drugs, with the potential for concomitant use as another dual-antiplatelet therapy for the prevention of recurrent thrombotic or ischemic events. Because they both are the substrates of carboxylesterase 2 (CES2), aspirin attenuated the metabolic activation of and platelet response to Vicagrel in mice treated with the two drugs concomitantly. In this study, we sought to clarify whether Vicagrel could affect platelet responses to aspirin and their underlying mechanisms. Plasma levels of aspirin and salicylic acid were determined by liquid chromatography-tandem mass spectrometry, inhibition of arachidonic acid (AA)-induced whole-blood platelet aggregation by aspirin was assessed with an aggregometer, and their antithrombotic effects were evaluated by arteriovenous shunt thrombosis model. The results showed that concomitant use of Vicagrel (5, 10, or 20 mg/kg) led to an average of 55% and 77% increases in systemic exposure of aspirin (Cmax and AUC0-t) and 2.8-fold increase in suppression of AA-induced platelet aggregation in mice when compared with use of aspirin alone. In the rat thrombus formation model, Vicagrel (1 mg/kg) enhanced inhibition of thrombosis formation by aspirin (5 mg/kg), but not vice versa. We conclude that Vicagrel increases platelet responses to aspirin and also enhances inhibition of thrombus formation of aspirin due to decreased CES2-catalyzed aspirin inactivation in rodents, and that an integrated net effect on thrombus formation in vivo is superior to inhibition of AA- or ADP-induced platelet aggregation ex vivo by either of the two drugs if taken concomitantly.
Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans
Front Pharmacol 2017 Nov 20;8:846.PMID:29209217DOI:10.3389/fphar.2017.00846.
Vicagrel, a structural analog of clopidogrel, is now being developed as a thienopyridine antiplatelet agent in a phase II clinical trial in China. Some studies have shown that Vicagrel undergoes complete first-pass metabolism in human intestine, generating the hydrolytic metabolite 2-oxo-clopidogrel via carboxylesterase-2 (CES2) and subsequently the active metabolite H4 via CYP450s. This study aimed to identify hydrolases other than CES2 that are involved in the bioactivation of Vicagrel in human intestine. This study is the first to determine that human arylacetamide deacetylase (AADAC) is involved in 2-oxo-clopidogrel production from Vicagrel in human intestine. In vitro hydrolytic kinetics were determined in human intestine microsomes and recombinant human CES and AADAC. The calculated contribution of CES2 and AADAC to Vicagrel hydrolysis was 44.2 and 53.1% in human intestine, respectively. The AADAC-selective inhibitors vinblastine and eserine effectively inhibited Vicagrel hydrolysis in vitro. In addition to CES2, human intestine AADAC was involved in Vicagrel hydrolytic activation before it entered systemic circulation. In addition, simvastatin efficiently inhibited the production of both 2-oxo-clopidogrel and active H4; further clinical trials are needed to determine whether the hydrolytic activation of Vicagrel is influenced by coadministration with simvastatin. This study deepens the understanding of the bioactivation and metabolism properties of Vicagrel in humans, which can help further understand the bioactivation mechanism of Vicagrel and the variations in the treatment responses to Vicagrel and clopidogrel.
Aspirin Attenuates the Bioactivation of and Platelet Response to Vicagrel in Mice
J Cardiovasc Pharmacol 2018 Nov;72(5):252-258.PMID:30358688DOI:10.1097/FJC.0000000000000622.
Vicagrel, a novel acetate analogue of clopidogrel, exerts more potent antiplatelet effect than clopidogrel in rodents. Relevant evidence indicated that aspirin and Vicagrel are the drug substrate for carboxylesterase 2. Accordingly, it is deduced that concomitant use of aspirin could attenuate the bioactivation of and platelet response to Vicagrel. To clarify whether there could be such an important drug-drug interaction, the differences in both the formation of Vicagrel active metabolite H4 and the inhibition of adenosine diphosphate-induced platelet aggregation by Vicagrel were measured and compared between mice treated with Vicagrel alone or in combination with aspirin. The plasma H4 concentration was determined by liquid chromatography-tandem mass spectrometry, and the inhibition of platelet aggregation by Vicagrel was assessed by whole-blood platelet aggregation. Compared with Vicagrel (2.5 mg·kg) alone, concurrent use of aspirin (5, 10, or 20 mg·kg) significantly decreased systemic exposure of H4, an average of 38% and 41% decrease in Cmax and AUC0-∞ in mice when in combination with aspirin at 10 mg·kg, respectively. Furthermore, concomitant use of aspirin (10 mg·kg) and Vicagrel (2.5 mg·kg) resulted in an average of 66% reduction in the inhibition of adenosine diphosphate-induced platelet aggregation by Vicagrel. We conclude that aspirin significantly attenuates the formation of Vicagrel active metabolite H4 and platelet response to Vicagrel in mice, and that such an important drug-drug interaction would appear in clinical settings if Vicagrel is taken with aspirin concomitantly when marketed in the future.
Platelet inhibitory activity, tolerability, and safety of Vicagrel, a novel thienopyridine P2Y12 inhibitor
Medicine (Baltimore) 2020 Jan;99(4):e18683.PMID:31977858DOI:10.1097/MD.0000000000018683.
Vicagrel is a new antiplatelet pro-drug based on clopidogrel sulfur lactone metabolites. The purpose of the study was to evaluate the safety, tolerability, and pharmacodynamics (PD) of Vicagrel in healthy Chinese subjects.This study was designed as a single-center, randomized, double-blind, placebo-controlled, single oral ascending dose study. Fifty nine subjects were assigned to 6 Vicagrel dose cohorts (5, 10, 20, 40, 60, and 75 mg), and 8 subjects were assigned to 75 mg clopidogrel. Within each Vicagrel dose cohort, the 10 subjects (9 in the 75 mg cohort) were randomized 4:1 to receive Vicagrel or placebo. Platelet function was assessed using VerifyNow P2Y12. ΔP2Y12 reaction units (ΔPRU) and percent inhibition platelet aggregation (%IPA) were used to evaluate the PD of Vicagrel.Although the number of adverse events (AEs) increased with Vicagrel dose, none were considered serious, suggesting that Vicagrel is safe and well-tolerated. The ΔPRU and %IPA patterns suggest that inhibition of ADP-induced platelet aggregation increased in a dose-dependent manner across the 10 to 40 mg dose range. The inhibitory effect was nearly complete at 4 hours (mean %IPA 87.9%-93.0%, mean ΔPRU 206.6-240.0) for doses of 40 to 75 mg of Vicagrel. In contrast, for 5 mg Vicagrel and 75 mg clopidogrel, there were no measurable effects on platelet aggregation throughout the study.The results suggest that Vicagrel at 40 to 75 mg inhibits ADP-induced platelet aggregation, with a fast onset of action and significantly greater potency than clopidogrel. These findings indicate that Vicagrel may be a highly effective and well-tolerated antiplatelet agent.